The thymus produces MHC-restricted abT cells that only recognize antigenic ligands in association with MHC or MHC-like molecules. We hypothesized that CD4 and CD8 coreceptors might be impose MHC-specificity on a broader abTCR repertoire during thymic selection because they bind and effectively sequester the tyrosine kinase Lck, thereby preventing TCR signaling by non-MHC ligands that do not engage either coreceptor. Using mice deficient for both CD4 and CD8 as well as MHC (Quad-deficient), we discoverd that ab thymocytes can be signaled by non-MHC ligands in the absence of coreceptors in vivo. In addition, we tested the critical role of coreceptors by introducing CD4 transgenes into Quad-deficient mice. Whereas sequestration of Lck by wild-type CD4 blocked signaling by non-MHC ligands on ab thymocytes, introducing a tailless form of CD4 didnt. We conclude that in the absence of Lck sequestration by coreceptors, thymocytes can be signaled by non-MHC ligands. Therefore, CD4 and CD8 impose MHC-specificity on a broad abTCR repertoire by preventing thymocytes to be selected by non-MHC ligands.